This invention relates to novel chemical compounds and to methods of treatment employing these compounds.
The class of compounds known as monoamine oxidase inhibitors (MAO inhibitors) has been employed in psychiatry for over twenty years for the treatment of depression [See Goodman and Gilman, The Pharmacological Basis of Therapeutics, 6th Ed., McMillan Publishing Co., Inc., N.Y., 1980, pages 427-430]. MAO inhibitors currently used in the United States for treating depression are tranylcypromine (PARNATE.RTM., SKF), phenelzine (NARDIL.RTM., Parke-Davis), and isocarboxazid (MARPLAN.RTM., Roche). In addition, another MAO inhibitor, pargyline (EUTRON.RTM., Abbott), is available for the treatment of hypertension [See Physicians' Desk Reference, 34th Ed., Medical Economics Co., Oradell, N.J., 1980, pages 1327-1328 (phenelzine), pages 1466-1468 (isocarboxazid), pages 1628-1630 (tranylcypromine), and pages 521-522 (pargyline)]. In addition to being used in treating depression, MAO inhibitors can be employed to treat other psychiatric disorders, such as phobic anxiety states.
Parkinson's syndrome is characterized by low levels of dopamine in the brain. The disease can be treated by the administration of exogenous dopa (or preferably L-dopa) which passes through the blood-brain barrier into the brain where it is transformed to dopamine which replenishes the endogenous monoamine. Dopamine is itself not effective for treating Parkinson's syndrome since it is not transported across the blood-brain barrier. It is known that the coadministration of a peripherally active aromatic amino decarboxylase (AADC) inhibitor (such as cardidopa) with L-dopa potentiates the effect of L-dopa and provides effective therapy at a lower dose of L-dopa. (See Phvsician's Desk Reference, Medical Economics Co., Oradell, N.J. p. 1198-1199). The potentiation of L-dopa occurs because the AADC inhibitor prevents the peripheral decarboxylation of L-dopa thereby increasing the amount of circulating L-dopa available for absorption into the brain. Prevention of the peripheral decarboxylation of dopa will also decrease the amount of circulating dopamine which is responsible for undesirable side effects. It is also known that the coadministration of certain MAO inhibitors (such as L-deprenyl) with L-dopa potentiates the effect of L-dopa and also provides effective therapy at a lower dose of L-dopa because the MAO inhibitor prevents the oxidative deamination of dopamine upon its formation from L-dopa.
It is believed that the MAO inhibitors act to alleviate psychiatric disorders, such as depression, by increasing the concentration of one or more biogenic monoamines in the brain or sympathetic nervous system. The monoamine oxidase enzyme (MAO) plays an important role in the metabolic regulation of the monoamines since it catalyzes the biodegradation of the monoamines through oxidative deamination. By inhibiting MAO, the degradation of the monoamines is blocked, and the result is an increase in the availability of the monoamines for their physiological functions. Among the physiologically active monoamines which are known substrates for MAO are: (a) the so-called "neurotransmitter" monoamines, such as the catecholamines (e.g. dopamine, epinephrine, and norepinephrine) and the indoleamines (e.g. tryptamine and 5-hydroxytryptamine), (b) the so-called "trace" amines (e.g. o-tyramine, phenethylamine, tele-N-methylhistamine), and (c) tyramine.
The usefulness of the MAO inhibitors in treating deression is limited because the administration of such agents can potentiate the pharmacological actions of certain food substances or drugs leading to dangerous and sometimes lethal effects. For example, persons receiving a MAO inhibitor must avoid the ingestion of foods which have a high tyramine content (such as cheese) because the MAO inhibitor will block the metabolic degradation of tyramine in the gut to produce high circulating levels of tyramine, consequent release of catechlolamines in the periphery, and finally serious hypertension. The potentiation by a MAO inhibitor of the pressor effect of tyramine arising from the ingestion of cheese, and the hypertensive episode produced thereby, are commonly known as the "cheese reaction" or "cheese effect". Moreover, persons on conventional MAO therapy cannot be given directly-acting sympathomimetic drugs (or precursors thereof) which are themselves substrates for MAO (e.g. dopamine, epinephrine, norepinephrine, or L-DOPA) or indirectly-acting sympathomimetic drugs (e.g. amphetamines or cold, hayfever, or weight control preparations that contain a vasoconstrictor). The potentiation of the pressor effect of indirectly-acting sympathomimetic drugs is especially profound. This is because such drugs act peripherally primarily by releasing catecholamines in nerve endings, and the concentration of the liberated catechlolamines will be dangerously elevated if the metabolic degradation of the catechoamines via MAO is blocked.
Biochemical and pharmacological studies indicate that the MAO enzyme exists in two forms known as "MAO Type A" (MAO-A) and "MAO Type B" (MAO-B). The two forms differ in their distribution in body organs, in their substrate specificity, and in their sensitivity to inhibitors. In general, MAO-A selectively oxidizes the so-called "neurotransmitter" monoamines (epinephrine, norepinephrine and 5-hydroxytrptamine) while MAO-B selectively oxidizes the "trace" monoamine (o-tyramine, phenethylamine, and tele-N-methylhistamine). Both MAO-A and MAO-B oxidize tyramine, tryptamine, and dopamine. However, in man, dopamine has been shown to be a preferred substrate for MAO-B. The forms also differ in their sensitivity to inhibition, and thus they can be preferentially inhibited depending upon the chemical structure of the inhibitor and/or the relative concentrations of the inhibitor and the enzyme. The MAO inhibitors currently sold in the United States for the therapy of depression (tranylcypromine, phenelzine, and isocarboxazid) are not preferential in their action upon MAO. However, various chemical compounds are known in the art to be preferential inhibitors of MAO, the most important being clorgyline, pargyline, and L-deprenyl which are all reported to be clinically effective antidepressant agents. MAO-A is preferentially inhibited by clorgyline, while MAO-B is preferentially inhibited by pargyline and L-deprenyl. The selectivity of an inhibitor for MAO-A or MAO-B in vivo will be dose-dependent, selectivity being lost as the dosage is increased. Clorgyline, pargyline, and L-deprenyl are selective inhibitors at lower dosages, but are less selective inhibitors at higher dosages. The literature concerning MAO-A and MAO-B and the selective inhibition thereof is extensive [See, for example, Goodman and Gilman, ibid, pages 204-205; Neff et al., Life Sciences, 14. 2061 (1974); Murphy, Biochemical Pharmacology, 27, 1889 (1978); Knoll, Chapter 10, pages 151-171 and Sandler, Chapter 11, pages 173-181, in Enzyme Inhibitors as Drugs, M. Sandler, Ed., McMillan Press Ltd , London 1980; Lipper et al, Psychopharmacology, 62, 123 (1979); Mann et al., Life Sciences, 26, 877 (1980); and various articles in Monoamines Oxidase: Structure, Function, and Altered Functions, T. Singer et al. Ed., Academic Press. N.Y., 1979].
Of the selective inhibitors of MAO, L-deprenyl is of interest since the "cheese effect" is not observed at the low dosages where preferential inhibition of MAO-B occurs [See Knoll, TINS, pages 111-113, May 1979]. This observation is not unexpected since the intestinal mucosa contains predominantly MAO-A which, because it is not inhibited, permits oxidation and removal of the ingested tyramine. The selectivity of L-deprenyl for MAO-B may account for its ability to potentiate L-DOPA for the treatment of Parkinson's disease without producing peripheral side effects, such as hypertension due to potentiation of pressor catecholamines [See Kees et al., Lancet, pages 791-795, Oct. 15, 1977 and Birkmeyer Lancet, pages 439-443, Feb. 26, 1977].
Previously the presence of an aryl moiety was believed necessary for potent MAO inhibition in those compounds which structurally mimic phenylethylamine, serotonin, the catecholamines, indoleamines, and trace amines such as the arylalkylhydrazines, propargylamines, phenylcyclopropylamines, and -methyltryptamines. Applicants have discovered a class of potent MAO inhibitors which do not structurally mimic the natural monoamines. In many cases, these novel, nonaromatic MAO inhibitors selectively inhibit MAO-B at low doses.